6 methyl 16 oxydelta4pregnenes and delta1, 4-pregnadienes



United States Patent 6 METHYL 16 OXYAPREGNENES AND A PREGNADIENES FrankH. Lincoln, Kalamazoo, William P. Schneider, Kalamazoo Township,Kalamazoo County, and Oldrich K. Sebek and George B. Spero, Kalamazoo,Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporationof Michigan No Drawing. Application February 19, 195s Serial No. 716,019

19 Claims. (Cl. 260-391.45)

is more particularly concerned with 6a-methyl-21-tluoro- ICC 217u-trihydroxy 4 pregnene-3,20-dione, 6a-inethyl-2lfluoro llfi,l6a,l7ct-,trihydroxy 1,4 pregnadiene-3,20-

I The present invention relates to steroid compounds and llfl,16oz,17ottrihydroxy-4-pregnene-3,20-dione, 6o -meth- 11fi,16a,17atrihydroxy-l,4-pregnadiene-3,20-dione, the

16-esters thereof, the ll-keto analogues and the 16-esters thereof, anda method for the production thereof.

The novel compounds of this invention are illustratively represented bythe following formula:

wherein the'1,2-carbon atom linkage is selected from the linkagesconsisting of single bond and double bond linkages, Y is selected' fromthe group consisting of hydrogen and fluorine, X is selected from thegroup consisting of the carbonyl radical C=O) and thefi-hydroxymethylene radical and R is selected from the group consistingof hydrogen and the acyl radical of an organic carboxylic 'acid,preferably a hydrocarbon carboxylic acid containing from one to twelvecarbon atoms, inclusive.

The new compounds, 6a-methyl-21-fluoro-l1p,16u,17atrihydroxy 4pregnene-3,20-dione, 6a-methyl-9a,2l-di- 6a-methyl 21fluoro-llfl,l6a,l7a-trihydroxy-L4-pregnadiene 3,20 dione,6a-methyl-9m,21- difiuoro-115,1611, 17a trihydroxy 1,4pregnadiene-3,20-dione, their 16- esters and the ll-keto analogues andthe esters thereof,

are highly active adrenocortical hormones having greater1,4-pregnadiene-3,20-dione, the l6-esters thereof, thellketo analoguesand the 16-esters thereof can' be given in oral, parenteral or topicalcompositions. The compounds can be administered to the animal organismin conventional dosage forms such as pills, tablets and capsules fororal use or in conventional liquid forms as are used with natural andsynthetic cortical steroid hormones for injection use. For topical usethey can be administered in the form of ointments, creams, lotions andthe like with or without co-acting antibiotics, germicides and the like.

The process of the present invention comprises microbiologicalhydroxylation of 6e-methyl-2l-fluoro-l 15,171:- dihydroxy 4pregnene-3,20-dione,6a-methyl-9a,2l-difluoro-I1p,17a-dihydroxy-4-pregnene-3,20-dione and theA -analogues thereof to produce the corresponding 16- hydroxy compounds.Esterification of the thus produced lo-hydroxylated compounds isproductive of the l6-esters. The corresponding ll-keto analogues ofthese l6-hydroxylated compounds are obtained by oxidation of thell-hydroxyl group of the above lo-esterified compounds with an oxidationagent such as chromic acid. If the free alcohols of the ll-ketocompounds are desired, the additional step of hydrolyzing the -16-esterssuch as with an alkali metal base is necessary.

Starting materials for the present invention are 60:-rnethyl-Zl-fiuoro-l1p,17a-dihydroxy 4 pregnene-3,20- dione, 6a-methyl9u,21 difiuoro-l 1B,l7a-dihydroxy-4- pregnene-3,20-dione, 6amethyl-Zl-fluoro-llfl,l7a-dihydroxy-l,4-pregnadiene-3,20-dione, and6u-methyl-9a,2ldifiuoro 11p,l7a-dihydroxy-1,4-pregnadiene-3,20-dione,prepared as described by Spero et al., J. Am. Chem. Soc., 79, 1515(1957). i

' In the bioconversion step of the present invention, the operationalconditions and reaction procedure and details may be those already knownin the art of steroid bioconversion as illustrated by the Murray et al.,U. S. Patent 2,602,769, issued July 8, 1952, utilizing, however, the

action of an organism of the genus Streptomyces. Among the species whichare useful in the fermentation of steroids are Streptomycesroseochromogenus (Waksman Collection3689), Streptomyces sp. (A. T. C. C.11009), and Streptomyces roseochromogenus (A. T. C(C. 3347).

The selected species of actinomycete is grown on a medium suitablycontaining assimilable non-steroidal carbon, illustrativelycarbohydrates, such as dextrose; assimilable nitrogen, illustrativelysoluble or insoluble proteins, peptones or amino acids; and mineralconstituents, illustratively sodium or ammonium phosphate and magnesiumsulfate. The medium may desirably have 'a pH before inoculation ofbetween about 6.5 to about 7.8 though a higher or lower pH may be used.A pH. of between about 6.8 and about 7.4 is preferred for the growth ofactinomycetesyand a temperature range from about 20 to about 35 degreescentigrade with about 20 to 32 degrees centigrade preferred.

The growth period required before the steroid to be fermented is exposedto the actinomycete does not appear to be critical, for example, thesteroid may be added either before sterilization of the medium, at thetime of inoculating the medium or at sometime later, for example, 24 or48 hours later. The addition of steroid substrate to be fermented may beaccomplished in any suitable manner, such as by dispersing the steroidsubstrate, either alone with a dispersing agent, or in solution in anorganic solvent. Either submerged or surface culture procedures may beused with facility, although submerged culture is preferred.

The temperature during the period of fermentation of the steroid may bethe same as that found suitable for the growth log transformed steroidis recovered from the fermentation reaction mixture by extracting thefermentation reaction mixture, including the fermentation liquor andmedium with an Organic solvent for steroids, for example, methylisopropyl ketone. methylene chloride, chloroform. carbon tetrachloride.ethylene chloride, trichloroethylene, ether, amyl acetate, benzene, andthe like. The fermentation li uor and m cel um can be separated and thenseparately extracted with suitable solvents. The extracts can becombined. either before or after washing with an alkaline solution,illustratively sodinm bicarbonate. suitably dr ed. as for e ample. o eranhydrous sodium sulfate, and the resulting purified trans ormed steroidobtained by recrystallization from organic solvents, by tritura ion orby chromatog aphy in order to is ate the thus obtained steroids from theother transformation products.

Bioconvers on of 6m methvl 21 fluoro 11p l7adihvdroxv 4 preanene 3.20dione. 6a.- methvl- 9a.21 difluoro 113171 dihydroxy 4 oregnene- 3.20dione, 6a methyl 21 fluoro "3.17m dihvdroxy 1.4 pregn diene 3.20 dione,and 6a methvl- 9.2l difiu ro 118.1701 dihvdroxy 1,4 precnadiene-3.2fl-dione accordinc to the fermentation procedure above descr bed. isproductive of 6a methyl 21 fluoro- 1lp,16a.l7a trihvdroxv 4 preanene3.20 dione, 6c methyl 911.21 difiuoro llp,l6a.l7a trihyd oxy- 4 pregnene3.20 dione, 6a methvl 21 fluorol 18.16:,171: trihvdroxv 1,4 nrelznadiene3.20 dione, and 6a methyl 901.21 difiuoro llfl.l6c,l7et trihydroxv 1.4preanadiene 3.20 dione, res ectively.

The lo-hydroxv ated compounds thus produced can be esten'fied to producethe corresponding 6-csters. This react on can be performed underesterification conditions known in the art. e. 3.. by the reaction ofthe hvdroxy compound with the selected acid halide. e. 3.. acid chlorideor acid bromide. the anhydride of a h drocarbon carboxylic acid. or byreaction with the selected acid, in the presence of an esterificationcat lvst or with an ester under ester exchange reaction cond tions. Reacion condltions which are not to aflect the labile l p-hy' roxy group. orthe 6-methvl group shou d be avoided. Compounds thu roduced include the16-acvoxv compounds represented by Formula 1 w ere n X isB-hydroxvmethylene radical and wherein R is the acvl radical of an orgnic carboxylic acid, preferably a hydrocarbon carboxvlie acid containingfrom one to twelve carbon atoms, inclusive,

e. 3., formic, propionic, butyric. isobutyric, valeric, isovaleric,trimethylacetic, Z-methylbutyric, 3-ethylbutyric, hexanoie,diethylacetic, triethylacetic, heptanoic, octanoic, a-ethylisovaleric,succinic, a cyclic acid, e. g., cyclopropylideneacetic,cyclopentylforrnic, cyclopentylacetic, p cyclohexylpropionic,cyclohexylformic, cyclohexylacetic, and aryl or alkaryl acid, e. g.,benzoic, 2-, 3- or 4-methylbenzoic, 2.3-, 2,4-, 2.5-, 2,6-, 3,4- and3,5-dimethylbenzoic, ethylbenzoic, 2,4,6 trimethylbenzoic, 2,4,6triethylbenzoic, a naphthoic, 3 methyl anaphthoic, ,an aralkyl acid, c.g., phenylacetic, phenylpropionic, diphenylacetic, triphenylacetic, anunsaturated acid, e. 3., acrylic, maleic, vinyl acetic, propiolic,undecolic, etc. Illustrative of he esters thus produced are prcgnadiene3,20 dione l6 acetate, 6:: methyl- 91,21 difiuoro 11fi,l6a,17a rihydroxy4 pregnene- 3,20 dione 16 acetate, methyl 9a,2l difiuoro- 11 fl,l6a,l7cztrihydroxy 1,4 prcgnadicne 3,20 dione 16-acetate, and the like.

The llp-hydroxyl of the thus produced l6-acylate compounds'can beoxidized to the corresponding 11- ketone with an oxidizing agent.Oxidizing agents such as chromic acid, potassium dichromate, ahalo-amide, and the like are operative. The oxidation can be carried outby a variety of methods, such as, for example, by oxidizing the saidllp-hydroxy steroid in acetic acidwater solution with chromium trioxide,sing molar quantities or a slight excess, such as from ten to thirtypercent excess, or by oxidizing with a haloamide or imide of an acid,such as N-bromoacetamide, N-chlorosuccinimide, or N-bromosuccinimidedissolved in pyridine, dioxane, or other suitable solvents. At theconclusion of the desired oxidation reaction, the excess oxidant isgenerally destroyed by addition of methyl alcohol, ethyl alcohol, andthe like for the chromic acid oxidant or a bisulfite forN-bromoacetamide, N-bromosuccinimide and other N-haloacylamides andimides. Thereafter, the resulting ll-keto product is recovered byconventional means, such as by dilution with water and extraction with awaterimmiscible solvent, e. g., methylene chloride, ether, benzene,toluene, ethyl acetate, or the like. Illustrative of the ll-ketol6-acylates thus produced are for example, 60: methyl 21 fluoro 1601,17:dihydroxy 4 pregnene 3,11,20 trione l6 acetate, 60: methyl 9a,2ldifiuoro16,l7a dihydroxy 4 pregnene 3,11,20- trione l6 acetate, 61 methyl 21fluoro 16a,l7adihydroxy 1,4 pregnadiene 3,11,20 trione 16 acetate, 6amethyl 911,21 difiuoro 1601,17: dihydroxy 1,4 prcgnadiene 3,11,20 trionel6 acetate, and the like.

The ll-keto 16-acylates thus produced may, if desired, be converted tothe free alcohols, i. e., Gar-methyl- 21 fiuoro 16a,l7u dihydroxy 4pregnene 3,11,20- trione, 6a methyl 9a,2l difiuoro l6a,17a dihydroxy 4pregncne 3,11,20 trionc, 6a methyl 21- fluoro l6a,l7a dihydroxy 1,4prcgnadiene 3,11,20- trione, and 6a methyl 9a,2l difiuoro16a,17adihydroxy 1,4 pregnadiene 3,11,20 trione. The alcohols areobtained from the acylates by hydrolysis in accordance with generalhydrolysis procedures known in the art. A preferred procedure is toemploy at least a molar equivalent of an alkali-metal bicarbonate in asubstantially oxygen-free solution of a mixture of a lower alkanol andwater. The hydrolysis reaction is carried out at a temperature betweenten and thirty degrees centigrade while protecting the mixture fromatmospheric oxygen.

. After the hydrolysis is complete, the reaction mixture is neutralizedwith an acid, e. g., acetic acid, and the hydrolyzcd product recoveredfrom the reaction mixture by evaporation and crystallization, extractionwith methylene chloride, or the like. The 16-esters when desired, canagain be prepared by esterification of the hydroxyl by cstcrificationprocedures hereinbefore described. The preferred esters are thosederived from an organic carboxylic acid preferably a hydrocarboncarboxylic acid con taining from one to twelve carbon atoms, inclusive.

The following examples are illustrative of the process and products ofthe present invention, but are not to be construed as limiting.

EXAMPLE 1 6a-methyl-21-fluoro-IIp,I6a,]7a-trihydr0xy-4-pregnene-3,20-dime One hundred milliliters of two percent cornsteep liquor ofsixty percent solids was adjusted to pH of 6.8 to 7.4 with sodiumhvdroxide and was sterilized at fifteen pounds pressure for thirtyminutes. To this, was added a similarly sterile solution of two grams ofCerelose (technicalgrade of dextrose) in four of water. This sterilemedium was inoculated with-a suspension of pores and mycelium ofStreptomyces roseochromogenus- (Waksman Collection No. 3689) and wasagitated on a rotary shaker for a period of 24 hours by which time agood growth of the organism had taken place. To this 24-hour culture,twenty milligrams of 6nt-fluO1'0-11fl,l7- dihydroxy-4-pregnene-3,20dionedissolved in 0.2 milliliter of dimethylformamide was added. Incubationof the steroid with the microorganism was maintained (with agitation)for five days, at which time the pH was 8.6. The fermentation broth wasthen separated into the mycelium and the beer by centrifugation. Themycelium was extracted first with two ZS-milliliter portions of acetoneand then with four successive 25-milliliter portions of methyl isopropylketone. The beer was also extracted with four successive 25-milliliterportions of methyl isopropyl -ketone. All of the extracts were combined,washed with twopereent aqueous sodium bicarbonate solution and withwater, dried with anhydrous sodium sulfate, and evaporated to dryness.The residue, which on paper chromatogram analysis showed the presence of6a-methyl 21 fluoro-1 1fi,16a,17u-trihydroxy-4- pregnene-3,20-dione, waspurified by chromatography over synthetic magnesium silicate (Florisil)and crystallization from acetone to give 6a-methyl-21-fluoro- 1 15,]6a,] 7a-trihydroxy-4-pregnene-3,20-dione.

Following the procedure of Example 1 above, but substituting 6amethyl-9u,21-difluoro-11p,17a-dihydroxy-4- pregnene-3,20-dione, 6amethyl-21-liuoro-l lfi,l7a-dihydroxy-l,4-pregnadiene-3,20-dione,' or6a-methyl-9a',2ldiliuoro-l1p,17a-dihydroxy-1,4 pregnadiene-3,20 dione asstarting material therein, is productive of 6a-methyl- 9a,21-difluorollfl,l6a,l7a trihydroxy 4 pregnene- 3,20-dione, 6c:methyl-Zl-fluoro-l1p,l6a,17a-trihydroxy- 1,4-pregnadiene-3,20-dione, and6a-methyl-9m,2l-difiuoro- 115,161,17a-trihydroxy-1,4-pregnadiene 3,20dione, respectively.

EXAMPLE 2 6a-methyI-21 -fluoro-1 118,16u,1 7a-trihydroxy-4-pregnene-3,20-dione 16-acetate A solution of 1.2 grams of6a-methyl-21-fluoro-11fl, l6a,17u-trihydroxy-4-pregnene-3,ZO-dione (fromExample 1) in twenty milliliters of pyridine and twenty milliliters ofacetic anhydride was allowed to stand at room temperature (about 25degrees centigrade) for eighteen hours and was then poured into 200milliliters of icewater. The resulting mixture was extracted withmethylene chloride and the extract was washed with dilute hydrochloricacid, dilute sodium bicarbonate, and water. After drying the solutionwith anhydrous sodium sulfate, the solvent was removed by evaporationand the residue was purified by chromatography over synthetic magnesiumsilicate (Florisil) and crystallization from acetone to give 6a-methyl21 fluoro-11p,16a,17a-trihydroxy-4- pregnene-3,20-dione 16-acetate.

Following the procedure of Example 2 above but substituting 6a methyl9m,21 difiuoro 11,B,16a,l7a trihydroxy 4 pregnene 3,20 dione, 6m methyl21- fiuoro 11fi,16a,-17oz trihydroxy 1,4 pregnadiene 3, 20 dione or 6stmethyl 901,21 -'difluoro 115,161, 1711 trihydroxy 1,4 pregnadiene 3,20dione as starting material therein is productive of 6a-methyl-9a,21-difluoro l1,8,l6a,17a trihydroxy 4 pregnene 3,20- dione 16 acetate, 60:methyl 21 fluoro 115,160, 17:: trihydroxy 1,4 pregnadiene 3,20 dione l6-acetate and 6a methyl 911,21 difluoro 1l}3,l6ot,17atrihydroxy 1,4pregnadiene 3,20 dione 16 acetate respectively.

Similarly, acylation of 6a-methyl-2l-difiuoro-115-1601,17u-trihydroxy-4-pregnene-3,20-dione with the appropriate acid anhydrideor acid chloride is productive of still other 16-acylates such as, forexample, 6u-methyl-2l-fiuoro- 1lp,1'6a,l7a trihydroxy 4 pregnene 3,20dione 16- propionate, 6a methyl 21 fluoro 115,161,170: trihydroxy 4pregnene 3,20 dione l6 butyrate, 6a-

methyl 21 fluoro llfl;16ot,17a trihydroxy 4 pregnene 3,20 dione 16valerate, 6a methyl 21- fiuoro 11fl,16a,17ct trihydroxy 4 r pregnene3,20 dione l6 hexanoate, 6a methyl 21 fluoro 1lfl,l6a, 17a trihydroxy 4pregnene 3,20 dione 16 laurate, 6a methyl 21 fluoro 11fl,16a,17cttrihydroxy 4- pregncne 3,20 dione 16 trimethylacetate, 6a methyl 21fluoro llfl,l6a,l7ot trihydroxy 4 pregnene- 3,20 dione 16 isobutyrate,6oz methyl 21 fluorollfl,16a,l7a trihydroxy pregnene 3,20 dione 16-isovalerate, 6a methyl 1 fluoro 11B,16a,17u trihydroxy 7 4 pregnene ,20dione 16-cyclohexane carboxylate, 6a methyl 21 fluoro11p,16a,17atrihydroxy 4 pregnene 3,20 dione 16 benzoate, 6a methyl 21fluoro 1lfi,16a,17a trihydroxy 4- pregnene 3,20 dione 16 phenylacetate,6a methyl- 21 fluoro 11fi,16a,17a trihydroxy 4 pregnene 3, 20 dione 16(p phenyl) propionate, 6a methyl- 21 fluoro 115,161,174; trihydroxy 4pregnene 3, 20 dione 16 (o-,m-',p-toluate), 6a methyl 21 fluorollfi,16a,l7oc trihydroxy 4 pregnene 3,20 dione 16 hemisuccinate, 6ozmethyl 21 fluoro 11p, l6a,l7a trihydroxy 4 pregnene 3,20 dione 1'6-hemiadipate, 6a methyl 21 fluoro llB,16u,l7atrihydroxy 4 pregnene 3,20dione l6 acrylate, 6a methyl 21 fi uoro llB,16ot,l7oz trihydroxy- 4pregnene 3,20 dione 16 undecylenate, 6a methyl- 2l fluoro 1lfl,16a,17atrihydroxy 4 p egnene- 3,20 dione l6 propiolate, 6a methyl 21 fluoro-11;3,16a,17a trihydroxy 4 pregnene 3,20 dione 16 cinnamate, 6a methyl 21fluoro llfl,l6a,l7atrihydroxy 4 pregnene 3,20 dione 16 maleate, 6amethyl 21 fluoro l1/8,l6a,l7oz trihydroxy 4- pregnene 3,20 dione 16citraconate.

Similarly, acylation of 6a-methyl-9a,2l-difluoro-l1p,

16a,17a trihydroxy 4 pregnene 3,20 dione, 6a-

methyl 21 fluoro 11fl,16a,17ct trihydroxy 1,4-

pregnadiene 3,20 dione or 6a methyl 9a,21 difiuoro 11p,16a,17atrihydroxy 1,4 pregnadiene 3, ZO-dione with the appropriate acylatingagent is productive of the corresponding l6-acylates. The preferredacylates are those corresponding to the acylates described above for6a-methyl-2l-fluoro-11B,16a,17a-trihyroxy-4- pregnene-3,20-dione.

EXAMPLE 3 6 a-methyl-ZI fluoro-I 6 0a,] 7 u-dihydmxy- I-pregnene-3,11,20-tri0ne 16-acetate To a solution of 0.5 gram of6a-methyl-21-fluoro- 1 1 3,1601,17a-trihydroxy-4-pregnene-3,20-dione16-acetate in twenty milliliters of acetic acid was added a solution of0.15 gram of chromium trioxide in one-half milliliter of water. Themixture was stirred and maintained at room temperature (about 25 degreescentigrade) for. a period of four hours. Thereafter the excess oxidantwas destroyed by the addition of 0.5 milliliter of methanol and themixture was poured into 100 milliliters of water and extracted withmethylene chloride. The extract was washed with dilute sodiumbicarbonate solution and with water, and was dried and evaporated todryness. The residue was crystallized from acetone to give Gut-methyl-21 fluoro 16a,17a dihydroxy 4 pregnene 3,11,20-

trione 16-acetate.

Following the procedure of Example 3 above but substituting 6a. methyl:,21-(111111010 1lB,16a,17a trihydroxy-4-pregnene-3,20-dione l6-acetate,6a-methyl-21- fluoro llfi,l6a,17a trihydroxy 1,4 pregnadiene- 3,20-dione16-acetate, or 6a-methyl-9a,21-difiuoro-11B, 16a,17a trihydroxy 1,4pregnadiene 3,20 dione 16-acetate as starting material therein isproductive of 7 61- methyl 91,21 dillll01'0-l6a,l7a dihydroxy 4-pregnene 3,11,20 trione 16 acetate, 6a methyl- 21 fluoro 16a,17dihydroxy 1,4 pregnadiene- 3,11,20-trione 16-acetate, and6a-methyl-9,21-difluoro- 16,17a dihydroxy 1,4 pregnadiene 3,11,20 trionel6-acetate, respectively.

Similarly oxidation of other llfl-hydroxy 16-ester compounds of Example2 is productive of the corresponding ll-keto 16-ester compounds. Thepreferred ll-lreto 16- ester compounds are those wherein the acylradical is that of an organic carboxylic acid, preferably a hydrocarboncarboxylic acid containing from one to twelve carbon atoms, inclusive.

Ear/mun 4 A solution of 1.2 grams of 6a-methyl-21-tluoro-l6a, 17dihydroxy 4 pregnene 3,11,20 trione 16- acetate, two grams of potassiumbicarbonate, 100 milliliters of methanol and fifteen milliliters ofwater was purged'with nitrogen and stirred at 25 degrees centigrade foreight hours. The solution was then neutralized by addition of aceticacid and the methanol was removed by distillation under reducedpressure. The residue was extracted with 100 milliliters of methylenechloride and the extract, after drying over sodium sulfate, waschromatographed over a column of eighty grams of synthetic magnesiumsilicate using Skellysolve B with increasing amounts of acetone forelution. The product fraction from the column was crystallized fromacetone to give 6a methyl 21 fluoro 161,17: dihydroxy 4-,.

pregnadiene-3,1l,20-trione, and 6a-methyl-9a,2l-difluoro- 16,l7u-dihydroxy-l ,4-pregnadiene-3,1 1,20-trione.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art, and the invention is therefore to be limited only by the scopeof the appended claims.

We claim: I

1. A l6-oxygenated steroid of the formula:

wherein the 1,2-carbon atom linkage is selected from the linkagesconsisting of single bond and double bond linkages, Y is selected fromthe group consisting of hydrogen and fluorine, X'is selected from thegroup consisting of the carbonyl radical and the p-hydroxymethyleneradical, and R is selected from the group consisting of hydrogen and theacyl radical of a hydrocarbon carboxylic acid containing from one totwelve carbon atoms, inclusive.

2. A 16-oxygenated pregnene of the formula:

wherein Y is selected from the group consisting of hydrogen andfluorine, X is selected from the group consisting of the carbonylradical and the [Shydroxymethylene radical, and R is selected froin thegroup consisting of hydrogen and the acyl radical of a hydrocarboncarboxylic acid containing from one to twelve carbon atoms, inclusive.

3. 6a methyl 21 fluoro 11p,16a,17a trihydroxy-tpregnene-3,20-dione.

4. 6a-methyl-9a,21-difiuoro-llp,l6u,17a-trihydroxy-4 pregnene-LZO-dione.

5. 6u-methyl-21-fluoro-16a,17 dihydroxy-4-pregnene- 3,11,20-trione.

, pregnene-3,l 1,20-trione.

7. 6a methyl 21 fluoro 11p,16a,l7-trihydroxy- 4-pregnene-3,20-dione16-acetate.

8; 6a methyl 9a,2l ditluoro- 113,161,171: -trihy-,droxy-4-pregnene-3,20-dione lfi-acetate.

pregnene-3,11,20-trione IG-acetate.

10. 6a methyl 91,21 difluoro 16,17nz-dihydroxy-4-pregnene-3,11,20-trione 16-acetate.

ll A IG-oxygenated pregnadiene of the formula:

CHI

CH1! CH: .03

OR Y wherein Y is selected from the group consisting of hydrogen andfluorine, X is selected from the group consisting of the carbonylradical and the p-hydroxymethylene radical, and R is selected from thegroup consisting of hydrogen and the acyl radical of a hydrocarboncarboxylic acid containing from one to twelve carbon atoms, inelusive.

12. 6a methyl 21 fluoro 1lp,16a,17a-trihydroxy-1,4-pregnadiene-3,20dione.

13. 6a methyl 9a,21difluoro-1lp,16a,17a-trihydroxy-1,4-pregnadiene-3,20-dione.

14. 6c methyl 21 fluoro l6a,17adihydroxy-1,4- pregnadiene-3,11,20-trione.

15. 6a methyl 91:,21 difluoro-16a,l7a-dihydroxy-1,4-pregnadiene-3,11,20-trione.

16. 6a methyl 21 fluoro 11p,16a,17-trihydroxy- 1,4-pregnadiene-3,20dione l6-acetate.

17. 6a methyl 901,21 difluoro llp,16a,l7atrihydroxy-l,4-pregnadiene-3,20-dione 16-acetate.

18. 6a methyl 21 fluoro l6a,l7a-dihydroxy 1,4-pregnadiene-3,ll,20-trione 16-acetate.

19. 6a: methyl 9a,21 difluoro-16a,17u-dihydroxy-1,4-pregnadiene-3,11,20-trione l6-acetate.

No references cited.

Patent No. 2,864,836 December 16, 1958 Frank H. Lincoln et al. It ishereby certified that error appears in the printed specification of theabove numbered patent requiring correction and that the said LettersPatent should read as corrected below.

Column 1, lines 27 to 39, the formula should appear as shown belowinstead of as in the patent-- CHQF 011 same column 1, lines 46 to 49inclusive, the B-hydroxymethylene radical should appear as shown belowinstead of as in the patent Signed and sealed this 7th day of July 1959.

[surf] Attest: KARL H. i INE, ROBERT C. WATSON, Attestz'ng Ojfioer.Commissioner of Patents.

1. A 16-OXYGENATED STEROID OF THE FORMULA: